Haimovitz-Friedman A, Kolesnick R N, Fuks Z
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA.
Br Med Bull. 1997;53(3):539-53. doi: 10.1093/oxfordjournals.bmb.a011629.
The sphingomyelin pathway is a ubiquitous, evolutionarily conserved signaling system initiated by hydrolysis of the plasma membrane phospholipid sphingomyelin to generate ceramide. Ceramide acts as a second messenger in activating the apoptotic cascade. Diverse cytokine receptors and environmental stresses utilize ceramide to signal apoptosis. In several cell systems ceramide links to the stress-activated protein kinase (SAPK)/c-jun kinase (JNK) cascade to signal apoptosis. The engagement of the sphingomyelin pathway in signaling apoptosis is tightly regulated by anti-apoptotic control mechanisms, and the balance between pro- and anti-apoptotic systems determines the magnitude of the apoptotic response in vitro and in vivo. This review describes the known elements and molecular ordering of ceramide-mediated apoptosis and the anti-apoptotic mechanisms that regulate its expression. Understanding of pro- and anti-apoptotic signaling involved in ceramide-mediated apoptosis and the modes of their co-ordinated function may yield opportunities for pharmacological interventions with potential for clinical applications.
鞘磷脂途径是一种普遍存在的、进化上保守的信号系统，由质膜磷脂鞘磷脂水解引发，生成神经酰胺。神经酰胺作为第二信使激活凋亡级联反应。多种细胞因子受体和环境应激利用神经酰胺来传递凋亡信号。在一些细胞系统中，神经酰胺与应激激活蛋白激酶（SAPK）/c-Jun激酶（JNK）级联反应相连以传递凋亡信号。鞘磷脂途径在凋亡信号传导中的参与受到抗凋亡控制机制的严格调控，促凋亡和抗凋亡系统之间的平衡决定了体内外凋亡反应的程度。本综述描述了神经酰胺介导的凋亡的已知元件和分子顺序以及调节其表达的抗凋亡机制。了解神经酰胺介导的凋亡中涉及的促凋亡和抗凋亡信号传导及其协同作用模式，可能为具有临床应用潜力的药物干预提供机会。
